Tacrolimus dose requirements in paediatric renal allograft recipients are characterized by a biphasic course determined by age and bone maturation

Knops, Noël; Herman, Jean; Dyck, Maria Van; Ramazani, Yasaman; Debbaut, Edward; Damme‐Lombaerts, Rita Van; Levtchenko, Elena; Heuvel, Lambertus P. van den; Fieuws, Steffen

doi:10.1111/bcp.13174

Cited by 11 publications

(17 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 3 In the early posttransplant phase in particular, frequent blood sampling, followed by dose adjustments, is required to ensure graft function and minimize potential adverse effects. In addition to the time-dependent changes in Tac pharmacokinetics during the first posttransplant year, Tac dose requirements may be affected by growth and development in the pediatric population, 4 prolonging the intensive monitoring phase in this population. TDM is therefore indicated at least every 3 months in pediatric patients and in many situations more often.…”

Section: Introductionmentioning

confidence: 99%

Tacrolimus Measured in Capillary Volumetric Microsamples in Pediatric Patients—A Cross-Validation Study

Kindem

Bjerre

Åsberg

et al. 2021

Therapeutic Drug Monitoring

View full text Add to dashboard Cite

Background: Therapeutic drug monitoring of tacrolimus (Tac) is mandatory in solid organ transplant (SOT) recipients. Finger-prick microsampling is more flexible and tolerable during the therapeutic drug monitoring of tacrolimus and has been shown to be applicable in adult SOT recipients. In this study, a previously validated method applying volumetric absorptive microsampling (VAMS) to measure Tac in adults was cross-validated in a pediatric population. Methods: Patients with SOT scheduled for standard posttransplant follow-up visits were recruited. Blood samples were obtained by trained phlebotomists using standard venipuncture and capillary microsampling, before the morning dose of Tac as well as 2 and 5 hours after dosing. Tac concentrations were quantified using liquid chromatography–tandem mass spectrometry. Concordance between Tac concentrations obtained with venipuncture and VAMS was evaluated using Passing–Bablok regression, calculation of absolute and relative differences, and percentage of samples within ±20% and ±30% difference. Results: A total of 39 SOT patients aged 4–18 years (22 male) were included. The median (range) predose venous blood concentration was 4.8 (2.6–13.6) mcg/L, with a difference between VAMS and venous blood samples of −0.2 ± 0.7 mcg/L. The relative mean difference was −1.3% [95% confidence interval (CI), −5.9% to 3.4%]. Ninety-two percent and 97% of the sample pairs demonstrated differences within ±20% and ±30%, respectively. Postdose (2 hours and/or 5 hours, n = 17) median concentration in venous blood was 7.9 (4.8–19.2) mcg/L. The difference between VAMS and venous blood samples was 0.1 ± 1.0 mcg/L, with a relative mean difference of −2.5% (95% confidence interval, −8.8% to 3.8%). Eighty-eight percent of the postdose sample pairs were within ±20% difference, and all were within ±30% difference. Conclusions: Tac concentrations can be accurately measured using VAMS technology in pediatric SOT recipients. This makes home-based Tac monitoring feasible in the pediatric population.

show abstract

Section: Introductionmentioning

confidence: 99%

Tacrolimus Measured in Capillary Volumetric Microsamples in Pediatric Patients—A Cross-Validation Study

Kindem

Bjerre

Åsberg

et al. 2021

Therapeutic Drug Monitoring

View full text Add to dashboard Cite

show abstract

“…3 A number of clinical characteristics have been shown to influence tacrolimus concentrations including: CYP3A5 genotype, age, hematocrit, weight, and donor status (living vs deceased). [4][5][6] CYP3A5 genotype is estimated to explain upwards of 50% of the inter-patient tacrolimus variability; however, the utilization of CYP3A5 genotype-guided personalized dosing strategies for tacrolimus has not been routinely implemented in clinical practice.…”

Section: Introductionmentioning

confidence: 99%

Evaluating the Impact of CYP3A5 Genotype on Post-Transplant Healthcare Resource Utilization in Pediatric Renal and Heart Transplant Recipients Receiving Tacrolimus

Pasternak¹,

Marshall²,

Gersch³

et al. 2021

PGPM

View full text Add to dashboard Cite

Purpose: CYP3A5 genotype is a significant contributor to inter-individual tacrolimus exposure and may impact the time required to achieve therapeutic concentrations and number of tacrolimus dose adjustments in transplant patients. Increased modifications to tacrolimus therapy may indicate a higher burden on healthcare resources. The purpose of this study was to evaluate whether CYP3A5 genotype was predictive of healthcare resource utilization in pediatric renal and heart transplant recipients. Patients and Methods: Patients <18 years of age with a renal or heart transplant between 6/1/2014-12/31/2018 and tacrolimus-based immunosuppression were included. Secondary use samples were obtained for CYP3A5 genotyping. Clinical data was retrospectively collected from the electronic medical record. Healthcare resource utilization measures included the number of dose changes, number of tacrolimus concentrations, length of stay, number of clinical encounters, and total charges within the first year post-transplant. Rejection and donor-specific antibody (DSA) formation within the first year were also collected. The impact of CYP3A5 genotype was evaluated via univariate analysis for the first year and multivariable analysis at 30, 90, 180, 270, and 365 days post-transplant. Results: Eighty-five subjects were included, 48 renal transplant recipients and 37 heart transplant recipients. CYP3A5 genotype was not associated with any outcomes in renal transplant, however, a CYP3A5 expresser phenotype was a predictor of more dose changes, more tacrolimus concentrations, longer length of stay, and higher total charges in heart transplant recipients. CYP3A5 genotype was not associated with rejection or DSA formation. Age and induction therapy were associated with higher total charges. Conclusion: CYP3A5 genotype may predict healthcare resource utilization in the first year post-transplant, although this may be mitigated by differences in tacrolimus management. Future studies should evaluate the impact of genotype-guided dosing strategies for tacrolimus on healthcare utilization resources.

show abstract

“…Using antipyrine as a more general marker of CYP activity, or the earlier mentioned probe drugs, a consistent pattern of GH administration on CYP activity could not be described . In line with these findings, Knops et al recently described that tacrolimus dose requirements in pediatric renal allograft recipients were characterized by a biphasic course, determined by age and bone maturation but not initiation of GH substitution itself …”

Section: Specific Issues Beyond Ontogeny Also Contribute To the Variamentioning

confidence: 99%

“…39,40 In line with these findings, Knops et al recently described that tacrolimus dose requirements in pediatric renal allograft recipients were characterized by a biphasic course, determined by age and bone maturation but not initiation of GH substitution itself. 41…”

Section: Specific Issues Beyond Ontogeny Also Contribute To the Variamentioning

confidence: 99%

Ontogeny of Phase I Metabolism of Drugs

Allegaert

Anker

2019

The Journal of Clinical Pharma

View full text Add to dashboard Cite

Capturing ontogeny of enzymes involved in phase I metabolism is crucial to improve prediction of dose‐concentration and concentration‐effect relationships throughout infancy and childhood. Once captured, these patterns can be integrated in semiphysiologically or physiology‐based pharmacokinetic models to support predictions in specific pediatric settings or to support pediatric drug development. Although these translational efforts are crucial, isoenzyme‐specific ontogeny‐based models should also incorporate data on variability of maturational and nonmaturational covariates (eg, disease, treatment modalities, pharmacogenetics). Therefore, this review provides a summary of the ontogeny of phase I drug‐metabolizing enzymes, indicating current knowledge gaps and recent progresses. Furthermore, we tried to illustrate that straightforward translation of isoenzyme‐specific ontogeny to predictions does not allow full exploration of scenarios of potential variability related to maturational (non–age‐related variability, other isoenzymes or transporters) or nonmaturational (disease, pharmacogenetics) covariates, and necessitates integration in a “systems” concept.

show abstract

Tacrolimus dose requirements in paediatric renal allograft recipients are characterized by a biphasic course determined by age and bone maturation

Cited by 11 publications

References 47 publications

Tacrolimus Measured in Capillary Volumetric Microsamples in Pediatric Patients—A Cross-Validation Study

Tacrolimus Measured in Capillary Volumetric Microsamples in Pediatric Patients—A Cross-Validation Study

Evaluating the Impact of CYP3A5 Genotype on Post-Transplant Healthcare Resource Utilization in Pediatric Renal and Heart Transplant Recipients Receiving Tacrolimus

Ontogeny of Phase I Metabolism of Drugs

Contact Info

Product

Resources

About